Characterization of Epilepsy Patients BEEP 2b

Epilepsy Clinical Trial

— BEEP2b  

Official title:

Characterization of Epilepsy Patients At-risk for Adverse Outcomes Related to Switching Antiepileptic Drug Products: BEEP 2b Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02707965
• Other study ID #: 15-107D
• Secondary ID: HHSF223201400188
• Status: Completed
• Phase: Phase 1
• Start date: June 8, 2017
• Est. completion date: September 4, 2018

Study information

• Verified date: March 2020
• Source: Food and Drug Administration (FDA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Some epilepsy patients are described as GB when they have worsened seizures or side effects related to switching between brand name and generic, or between generic antiepileptic drug (AED) products. In concert with Aim 1 (protocol BEEP2a), this study will uncover possible reasons for patient problems with the drug switching. Factors that will be studied in GB epilepsy patients include physiologic, psychological, and genetic factors, including in this protocol whether brand and generic AEDs are pharmacokinetically similar in GB individuals.

Description:

This pilot study is exploratory research to characterize the "generic brittle" (GB) patient and to identify major causes for generic brittleness in epilepsy patients who are sensitive to antiepileptic drug (AED) formulation changes.

The primary aim of this BEEP2b study is to perform individual pharmacokinetic (PK) similarity testing of brand and generic AEDs in "probably GB" patients (N=12),who were selected on the basis of having GB-defining factors from the BEEP2a study, in order to confirm whether these factors are predictive of a generic brittle response to product switching. The study design involves a randomized, double-blind, multiple-dose, complete four-way replicate crossover design in which one brand and one generic will be compared in each patient from the patient's own AED regimen. Associated adverse events (i.e. seizures and side effects) will also be assessed. Bioequivalence (BE) will not be assessed. Rather, about nine AEDs are expected to be collectively evaluated. Generic brittleness anticipates that, for individual subjects, brand and generic may be the same or different, depending upon the underlying basis for generic brittleness. This exploratory research is focused on understanding individual patient attributes that contribute to GB, and is not focused on either product development or comparison of specific products.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: September 4, 2018
• Est. primary completion date: August 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 76 Years

Eligibility

Inclusion Criteria:

1. Subject previously completed BEEP2a study, found to be probably GB, and able to provide informed consent or subject's legally authorized representative is able to provide informed consent.

2. Subject is male or female between 18 and 76 years of age inclusive.

3. Subject has a diagnosis of epilepsy including focal or primary generalized epilepsy.

4. Subject is taking at least one study antiepileptic drug for the treatment of epilepsy.

5. Subject is an acceptable candidate for venipuncture.

6. Subject is willing to be switched between brand and generic drug.

7. Subject is willing to stop all non-routine OTC medications for 24 hours prior to and during pharmacokinetic study visits.

8. Subject is willing to maintain stable doses of all other AEDs, including Vagus Nerve Stimulation parameters for the duration of the study.

Exclusion Criteria:

1. Subject has any medical condition, including a progressive neurological condition, which in the opinion of the investigator, could jeopardize the subject's health or would compromise the subject's ability to participate in the trial.

2. Subject has a history of alcohol or drug abuse, which in the opinion of the investigator, could jeopardize the subject's health or would compromise the subject's ability to participate in this trial.

3. Subject has a history of previous or current significant psychiatric disorder that would interfere with conduct of the study.

4. Subject is pregnant or lactating.

5. Subject has severe liver impairment as assessed by alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels =10 times the upper limit of normal (ULN).

6. Subject has severe renal impairment as assessed by creatinine clearance lower than 30mL/min, using the Cockcroft-Gault formula.

7. Female subjects of childbearing potential will not be eligible to participate who are unwilling or unable to use a medically acceptable method of contraception throughout the entire study period and for one week after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or her partner are: condom with spermicide, diaphragm with spermicide, IUD without progesterone, vaginal spermicidal suppository, surgical sterilization of their partner(s) or abstinence.

8. Subject is not willing or able to be adherent to study protocol (e.g. study medication dosing and any interacting comedication).

Related Conditions & MeSH terms

• Epilepsy

Intervention

Drug:
• Oxcarbazepine (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Divalproex Sodium (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Carbamazepine (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Lamotrigine (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• levetiracetam (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Topiramate (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Zonisamide (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Phenytoin sodium (brand name vs generic drugs)
This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.

Locations

Country	Name	City	State
United States	University of Maryland, Baltimore	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Food and Drug Administration (FDA)	University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (13)

Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007 Mar;48(3):464-9. — View Citation

Bialer M, Midha KK. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia. 2010 Jun;51(6):941-50. doi: 10.1111/j.1528-1167.2010.02573.x. Epub 2010 Apr 8. Review. — View Citation

Cawello W, Bonn R. No pharmacokinetic interaction between lacosamide and valproic acid in healthy volunteers. J Clin Pharmacol. 2012 Nov;52(11):1739-48. doi: 10.1177/0091270011426875. Epub 2011 Dec 8. — View Citation

Elger C, Bialer M, Falcão A, Vaz-da-Silva M, Nunes T, Almeida L, Soares-da-Silva P. Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers. Epilepsia. 2013 Aug;54(8):1453-61. doi: 10.1111/epi.12242. Epub 2013 Jun 12. — View Citation

Fitzgerald CL, Jacobson MP. Generic substitution of levetiracetam resulting in increased incidence of breakthrough seizures. Ann Pharmacother. 2011 May;45(5):e27. doi: 10.1345/aph.1P765. Epub 2011 Apr 26. — View Citation

Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW; American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007 Apr 17;68(16):1249-50. — View Citation

McAuley JW, Chen AY, Elliott JO, Shneker BF. An assessment of patient and pharmacist knowledge of and attitudes toward reporting adverse drug events due to formulation switching in patients with epilepsy. Epilepsy Behav. 2009 Jan;14(1):113-7. doi: 10.1016/j.yebeh.2008.08.009. Epub 2008 Sep 26. — View Citation

Rascati KL, Richards KM, Johnsrud MT, Mann TA. Effects of antiepileptic drug substitutions on epileptic events requiring acute care. Pharmacotherapy. 2009 Jul;29(7):769-74. doi: 10.1592/phco.29.7.769. — View Citation

Rouits E, Burton I, Guénolé E, Troenaru MM, Stockis A, Sargentini-Maier ML. Pharmacokinetics of levetiracetam XR 500mg tablets. Epilepsy Res. 2009 Apr;84(2-3):224-31. doi: 10.1016/j.eplepsyres.2009.02.001. Epub 2009 Mar 4. — View Citation

Shaw SJ, Hartman AL. The Controversy over Generic Antiepileptic Drugs. J Pediatr Pharmacol Ther. 2010 Apr;15(2):81-93. — View Citation

Stevens RE, Limsakun T, Evans G, Mason DH Jr. Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulations (Carbatrol and Tegretol-XR). J Pharm Sci. 1998 Dec;87(12):1531-4. — View Citation

Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple R, Polli JE. Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015 Sep;56(9):1415-24. doi: 10.1111/epi.13095. Epub 2015 Jul 23. — View Citation

Zachry WM 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia. 2009 Mar;50(3):493-500. doi: 10.1111/j.1528-1167.2008.01703.x. Epub 2008 Jun 26. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean AUC0-last_ss (Test vs. Reference)	Average AUC (area under the drug plasma curve.	For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
Primary	Mean Cmax_ss (Test vs. Reference)	Average maximum drug plasma concentration;	For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
Primary	Mean Cmin_ss (Test vs. Reference)	Average minimum drug plasma concentration (Cmin);	For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
Secondary	Number of Adverse Events	summed for each anti-epileptic drug from when taking brand and generic.	Through the approximately 2 week period when the treatment is given.
Secondary	Number of Seizures Reported	Number of seizures reported in all groups	Through the approximately 2 week period when the treatment is given.